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BACKGROUND: Physical activity is associated with lower colorectal cancer (CRC) risk, but its association with molecular subtypes defined by genetic and epigenetic alterations of the disease is unclear. Such information may enhance the understanding of the mechanisms related to the benefits of physical activity.METHODS: Pooled observational (ncases=5,386, ncontrols=6,798; nstudies=5) and genome-wide association data (ncases=8,178, ncontrols=10,472; nstudies=5) were utilised. We used multivariable logistic regression models and Mendelian randomisation (MR) to assess the association between physical activity and the risk of CRC subtypes defined by individual tumour markers (and marker combinations), namely microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, BRAF and KRAS mutations. We used case-only analysis to test for differences between molecular subtypes. We applied Bonferroni correction to account for multiple tests.RESULTS: In the pooled observational analysis, higher levels of physical activity were associated with lower CRC risk (ORObs-per 1SD=0.94, 95%CI 0.90-0.97), with an association that was stronger in males (ORObs-per 1SD=0.91, 95%CI 0.87-0.96) than in females (ORObs-per 1SD=0.97, 95%CI 0.91-1.03) (Pinteraction=0.04). Higher physical activity was associated with a lower risk of CRC across all molecular subtypes, especially in males. There was no difference in the associations by subtypes by pooled observational or MR analyses. The findings did not differ by study design, anatomical site, and early or late age onset of CRC.CONCLUSIONS: Our findings suggest that physical activity is not differentially associated with the four major molecular subtypes involved in colorectal carcinogenesis, indicating that its benefits extend broadly across colorectal cancer pathogenesis.